Drug-Induced Epigenomic Plasticity Reprograms Circadian Rhythm Regulation to Drive Prostate Cancer toward Androgen Independence

Simon Linder, Marlous Hoogstraat, Suzan Stelloo, Nils Eickhoff, Karianne Schuurman, Hilda de Barros, Maartje Alkemade, Elise M. Bekers, Tesa M. Severson, Joyce Sanders, Chia Chi Flora Huang, Tunc Morova, Umut Berkay Altintas, Liesbeth Hoekman, Yongsoo Kim, Sylvan C. Baca, Martin Sjöström, Anniek Zaalberg, Dorine C. Hintzen, Jeroen de JongRoelof J.C. Kluin, Iris de Rink, Claudia Giambartolomei, Ji Heui Seo, Bogdan Pasaniuc, Maarten Altelaar, René H. Medema, Felix Y. Feng, Amina Zoubeidi, Matthew L. Freedman, Lodewyk F.A. Wessels, Lisa M. Butler, Nathan A. Lack, Henk van der Poel (Corresponding author), Andries M. Bergman (Corresponding author), Wilbert Zwart (Corresponding author)

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In prostate cancer, androgen receptor (AR)–targeting agents are very effective in various disease stages. However, therapy resistance inevitably occurs, and little is known about how tumor cells adapt to bypass AR suppression. Here, we performed integrative multiomics analyses on tissues isolated before and after 3 months of AR-targeting enzalutamide monotherapy from patients with high-risk prostate cancer enrolled in a neoadjuvant clinical trial. Transcriptomic analyses demonstrated that AR inhibition drove tumors toward a neuroendocrine-like disease state. Additionally, epigenomic profiling revealed massive enzalutamide-induced reprogramming of pioneer factor FOXA1 from inactive chromatin sites toward active cis-regulatory elements that dictate prosur-vival signals. Notably, treatment-induced FOXA1 sites were enriched for the circadian clock component ARNTL. Posttreatment ARNTL levels were associated with patients’ clinical outcomes, and ARNTL knockout strongly decreased prostate cancer cell growth. Our data highlight a remarkable cistromic plasticity of FOXA1 following AR-targeted therapy and revealed an acquired dependency on the circadian regulator ARNTL, a novel candidate therapeutic target. SIGNIFICANCE: Understanding how prostate cancers adapt to AR-targeted interventions is critical for identifying novel drug targets to improve the clinical management of treatment-resistant disease. Our study revealed an enzalutamide-induced epigenomic plasticity toward prosurvival signaling and uncovered the circadian regulator ARNTL as an acquired vulnerability after AR inhibition, presenting a novel lead for therapeutic development.

Original languageEnglish
Pages (from-to)2074-2097
Number of pages24
JournalCancer Discovery
Issue number9
Publication statusPublished - 1 Sept 2022

Bibliographical note

Funding Information:
This work was supported by Movember (NKI01 to A.M. Bergman and W. Zwart), KWF Dutch Cancer Society (10084 ALPE to A.M. Bergman and W. Zwart), KWF Dutch Cancer Society/Alpe d’HuZes Bas Mulder Award (NKI 2014-6711 to W. Zwart), the Netherlands Organization for Scientific Research (NWO-VIDI-016.156.401 to W. Zwart), Department of Defense (W81XWH-19-1-0565 to W. Zwart), and Astellas Pharma (to W. Zwart, A.M. Bergman, and H. van der Poel). The authors thank the NKI-AVL Core Facility Molecular Pathology and Biobanking, the NKI Proteomics/Mass Spectrometry facility (supported by the Dutch NWO X-omics Initiative), and the NKI Preclinical Intervention Unit (MCCA) for experimental assistance; the NKI Genomics Core facility for next-generation sequencing and bioinformatics support; and the NKI Research High Performance Computing facility for computational infrastructure. We also thank all Zwart/Bergman lab members for fruitful discussions and technical advice. Finally, we thank all patients and clinical staff who were involved in the DARANA trial.

Funding Information:
S.C. Baca reports other support from Precede Biosciences outside the submitted work. F.Y. Feng reports personal fees from Janssen Oncology, Bayer, Exact Sciences, Blue Earth Diagnostics, Myovant Sciences, Roivant Sciences, Astellas Pharma, Foundation Medicine, Varian, Bristol Meyers Squibb, Bluestar Genomics, Novartis, and Tempus and other support from PFS Genomics, SerImmune, and Artera AI outside the submitted work. M.L. Freedman reports other support from Precede Bio outside the submitted work. L.F.A. Wessels reports grants from Genmab outside the submitted work. N.A. Lack reports grants, personal fees, and other support from Nido Biosciences and grants from AstraZeneca outside the submitted work. H. van der Poel reports grants from Astellas during the conduct of the study. A.M. Bergman reports grants from Movember, the Dutch Cancer Society, and Astellas Pharma during the conduct of the study, as well as personal fees from Astellas Pharma outside the submitted work. W. Zwart reports grants from Astellas Pharma during the conduct of the study, as well as grants and personal fees from Astellas Pharma, and grants from AstraZeneca outside the submitted work. No disclosures were reported by the other authors.

Publisher Copyright:
©2022 American Association for Cancer Research.


  • ARNTL Transcription Factors/genetics
  • Androgens/pharmacology
  • Cell Line, Tumor
  • Circadian Rhythm
  • Drug Resistance, Neoplasm/genetics
  • Epigenomics
  • Humans
  • Male
  • Nitriles/therapeutic use
  • Prostatic Neoplasms, Castration-Resistant/drug therapy
  • Receptors, Androgen/genetics


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